Therapie der Amyotrophen Lateralsklerose

ZUSAMMENFASSUNG

Die amyotrophe Lateralsklerose (ALS) stellt eine unheilbare neurodegenerative Erkrankung dar und ist durch eine Degeneration der Motoneuronen im Kortex und im Rückenmark charakterisiert. Durch einen rasch progredienten Abbau der Skelettmuskulatur, insbesondere der Atem- und Schluckmuskulatur, ist die Prognose der Patienten mit ca. 2 bis 5 Jahren nach Symptombeginn sehr eingeschränkt. Es bestehen unterschiedliche Hypothesen über die Pathophysiologie der ALS wie eine Glutamat-Exzitotoxizität, mitochondriale Störungen oder eine Degeneration der Motoneurone aufgrund von Proteinaggregatablagerungen im Zytoplasma. Ebenso konnten einige genetische Veränderungen mit der ALS in Verbindung gebracht werden. Aktuell stellt Riluzol das einzige zugelassene Medikament zur Behandlung der ALS in Deutschland dar, daneben wird in ALS-Zentren der Radikalfänger Edaravone im Off-label-use eingesetzt. Beide Medikamente sorgen nur für eine eingeschränkte körperliche Besserung bzw. einen Überlebensvorteil von wenigen Monaten. Daher werden weitere Therapiestudien u. a. an ALS-Zentren in Deutschland durchgeführt, die in dieser Übersichtsarbeit vorgestellt werden sollen.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and shows a degeneration of motor neurons in motor cortex and spinal cord. The prognosis of the disease is restricted with a survival of 2 to 5 years after symptom onset caused by a progressive skeletal muscle reduction, especially of respiratory and swallowing muscles. Hypotheses regarding the pathophysiology of ALS include glutamate excitotoxicity, mitochondrial disruption or degeneration of motor neurons by protein aggregation in the cytoplasm. Likewise, genetic mutations have been associated with ALS. Currently, riluzole is the only approved drug in the treatment of ALS in Germany, while the radical scavenger edaravone is applied in ALS centres in off label use. Both drugs lead to a moderate physical improvement and survival benefit of a few months, respectively. Therefore, further therapy studies are ongoing inter alia at German ALS centres and are presented in this review article.

Schlüsselwörter

Amyotrophe Lateralsklerose - Therapie - Edaravone - Riluzol - Biomarker

Key Words

Amyotrophic lateral sclerosis - therapy - edaravone - riluzole - biomarker

• Literatur

• 1 Chio A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E. et al Prognostic factors in ALS: A critical review. Amyotroph Lateral Scler 2009; 10 (5–6) 310-23.
• 2 Logroscino G, Traynor BJ, Hardiman O, Chio A, Mitchell D, Swingler RJ. et al Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry 2010; 81 (04) 385-90.
• 3 Broussalis E, Grinzinger S, Kunz AB, Killer-Oberpfalzer M, Haschke-Becher E, Hartung HP. et al Late age onset of amyotrophic lateral sclerosis is often not considered in elderly people. Acta Neurol Scand 2018; 137 (03) 329-34.
• 4 Peters OM, Brown RH. Amyotrophic Lateral Sclerosis. Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders; 2015: 262-80.
• 5 Verde F, Steinacker P, Weishaupt JH, Kassubek J, Oeckl P, Halbge-bauer S. et al Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2019; 90 (02) 157-64.
• 6 Shepheard SR, Wuu J, Cardoso M, Wiklendt L, Dinning PG, Chataway T. et al Urinary p75(ECD): A prognostic, disease progression, and pharmacodynamic biomarker in ALS. Neurology. 2017; 88 (012) 1137-43.
• 7 Boylan KB, Glass JD, Crook JE, Yang C, Thomas CS, Desaro P. et al Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as a potential prognostic biomarker in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013; 84 (04) 467-72.
• 8 Keizman D, Rogowski O, Berliner S, Ish-Shalom M, Maimon N, Nefussy B. et al Low-grade systemic inflammation in patients with amyotrophic lateral sclerosis. Acta Neurol Scand 2009; 119 (06) 383-9.
• 9 Ilzecka J. Granzymes A and B levels in serum of patients with amyotrophic lateral sclerosis. Clin Biochem 2011; 44 (8–9) 650-3.
• 10 Hwang CS, Liu GT, Chang MD, Liao IL, Chang HT. Elevated serum autoantibody against high mobility group box 1 as a potent surrogate biomarker for amyotrophic lateral sclerosis. Neurobiol Dis 2013; 58: 13-8.
• 11 DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ. et al Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011; 72 (02) 245-56.
• 12 Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A. et al Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993; 362 (6415) 59-62.
• 13 Kwiatkowski Jr. TJ, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C. et al Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009; 323 (5918) 1205-8.
• 14 Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT. et al Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006; 314 (5796) 130-3.
• 15 Project Min EALSSC CHCHD10 variants in amyotrophic lateral sclerosis: Where is the evidence?. Ann Neurol 2018; 84 (01) 110-6.
• 16 Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Muller K. et al Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci 2015; 18 (05) 631-6.
• 17 Muller K, Brenner D, Weydt P, Meyer T, Grehl T, Petri S. et al Comprehensive analysis of the mutation spectrum in 301 German ALS families. J Neurol Neurosurg Psychiatry 2018; 89 (08) 817-27.
• 18 Byrne S, Elamin M, Bede P, Shatunov A, Walsh C, Corr B. et al Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol 2012; 11 (03) 232-40.
• 19 Milanese M, Zappettini S, Onofri F, Musazzi L, Tardito D, Bonifacino T. et al Abnormal exocytotic release of glutamate in a mouse model of amyotrophic lateral sclerosis. J Neurochem 2011; 116 (06) 1028-42.
• 20 Shaw PJ, Ince PG. Glutamate, excitotoxicity and amyotrophic lateral sclerosis. J Neurol 1997; 244 (Suppl. 02) S3-14.
• 21 Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995; 38 (01) 73-84.
• 22 Pickles S, Destroismaisons L, Peyrard SL, Cadot S, Rouleau GA, Brown Jr. RH. et al Mitochondrial damage revealed by immunoselection for ALS-linked misfolded SOD1. Hum Mol Genet 2013; 22 (019) 3947-59.
• 23 Wiedemann FR, Manfredi G, Mawrin C, Beal MF, Schon EA. Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. J Neurochem 2002; 80 (04) 616-25.
• 24 Ling SC, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 2013; 79 (03) 416-38.
• 25 Dewey CM, Cenik B, Sephton CF, Johnson BA, Herz J, Yu G. TDP-43 aggregation in neurodegeneration: are stress granules the key?. Brain Res 2012; 1462: 16-25.
• 26 Ludolph AC, Brettschneider J. TDP-43 in amyotrophic lateral sclerosis – is it a prion disease?. Eur J Neurol 2015; 22 (05) 753-61.
• 27 Muller HP, Kassubek J. MRI-Based Mapping of Cerebral Propagation in Amyotrophic Lateral Sclerosis. Front Neurosci 2018; 12: 655
• 28 Bakkar N, Kovalik T, Lorenzini I, Spangler S, Lacoste A, Sponaugle K. et al Artificial intelligence in neurodegenerative disease research: use of IBM Watson to identify additional RNA-binding proteins altered in amyotrophic lateral sclerosis. Acta Neuropathol 2018; 135 (02) 227-47.
• 29 NEALS Sample Repository 2019 [Available from https://www.neals.org/for-als-researchers/neals-sample-repository
• 30 Oberstadt M, Stieler J, Simpong DL, Romuss U, Urban N, Schaefer M. et al TDP-43 self-interaction is modulated by redox-active compounds Auranofin, Chelerythrine and Riluzole. Sci Rep 2018; 8 (01) 2248
• 31 Naujock M, Stanslowsky N, Bufler S, Naumann M, Reinhardt P, Sterneckert J. et al 4-Aminopyridine Induced Activity Rescues Hypoexcitable Motor Neurons from Amyotrophic Lateral Sclerosis Patient-Derived Induced Pluripotent Stem Cells. Stem Cells 2016; 34 (06) 1563-75.
• 32 Doble A. The pharmacology and mechanism of action of riluzole. Neurology 1996; 47 (6 Suppl 4) S233-41.
• 33 Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med 1994; 330 (09) 585-91.
• 34 Lacomblez L, Bensimon G, Leigh PN, Guillet P, Powe L, Durrleman S. et al A confirmatory dose-ranging study of riluzole in ALS. ALS/Riluzole Study Group-II. Neurology 1996; 47 (6 Suppl 4) S242-50.
• 35 Riluzol-Suspension vereinfacht die Therapie bei vielen Patienten. Aerztezeitung 2017
• 36 D’Amico E, Factor-Litvak P, Santella RM, Mitsumoto H. Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis. Free Radic Biol Med 2013; 65: 509-27.
• 37 Ito H, Wate R, Zhang J, Ohnishi S, Kaneko S, Ito H. et al Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp Neurol 2008; 213 (02) 448-55.
• 38 Edaravone Acute Infarction Study G. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis 2003; 15 (03) 222-9.
• 39 Enomoto M, Endo A, Yatsushige H, Fushimi K, Otomo Y. Clinical Effects of Early Edaravone Use in Acute Ischemic Stroke Patients Treated by Endovascular Reperfusion Therapy. Stroke 2019; 50 (03) 652-8.
• 40 Yoshino H, Kimura A. Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study). Amyotroph Lateral Scler 2006; 7 (04) 241-5.
• 41 Abe K, Itoyama Y, Sobue G, Tsuji S, Aoki M, Doyu M. et al Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener 2014; 15 (7–8) 610-7.
• 42 Takahashi F, Takei K, Tsuda K, Palumbo J. Post-hoc analysis of MCI186-17, the extension study to MCI186-16, the confirmatory double-blind, parallel-group, placebo-controlled study of edaravone in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2017; 18 (sup1) 32-9.
• 43 Writing G, Edaravone ALSSG. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2017; 16 (07) 505-12.
• 44 Writing Group On Behalf Of The Edaravone Als 18 Study G. Exploratory double-blind, parallel-group, placebo-controlled study of edaravone (MCI-186) in amyotrophic lateral sclerosis (Japan ALS severity classification: Grade 3, requiring assistance for eating, excretion or ambulation). Amyotroph Lateral Scler Frontotemporal Degener 2017; 18 (sup1) 40-8.
• 45 Grehl T, Grosskreutz J. Koch et al. Handlungsempfehlung zum Medikament Edaravone in den USA 2017 [Available from. https://www.krupp-krankenhaus.de/fileadmin/pdfs/arztinfo/handlungsempfehlung-edaravone-als.pdf.
• 46 Parkinson Study G. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol 2002; 59 (012) 1937-43.
• 47 Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A. et al A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009; 361 (013) 1268-78.
• 48 Waibel S, Reuter A, Malessa S, Blaugrund E, Ludolph AC. Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model. J Neurol 2004; 251 (09) 1080-4.
• 49 Ludolph AC, Schuster J, Dorst J, Dupuis L, Dreyhaupt J, Weishaupt JH. et al Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial. Lancet Neurol 2018; 17 (08) 681-8.
• 50 Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 2004; 10 (04) 402-5.
• 51 Benatar M, Wuu J, Andersen PM, Atassi N, David W, Cudkowicz M. et al Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS. Neurology 2018; 90 (07) e565-e74.
• 52 Arimoclomol in Amyotrophic Lateral Sclerosis 2019 [Available from: https://clinicaltrials.gov/ct2/show/record/NCT03491462.
• 53 Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients with ALS (REFALS) 2019 [Available from: https://clinicaltrials.gov/ct2/show/NCT03505021.
• 54 Altenberger J, Gustafsson F, Harjola VP, Karason K, Kindgen-Milles D, Kivikko M. et al Levosimendan in Acute and Advanced Heart Failure: An Appraisal of the Clinical Database and Evaluation of Its Therapeutic Applications. J Cardiovasc Pharmacol 2018; 71 (03) 129-36.
• 55 Al-Chabali A, Shaw P, Leigh PN. et al. Oral levosimendan (ODM-109): Key placebo-controlled results from the phase 2 study in ALS patients with SVC between 60–90 % predicted at screening. 28th International Symposim on ALS/MND; Boston: USA2017
• 56 Cortez LM, Campeau J, Norman G, Kalayil M, Van der Merwe J, McKenzie D. et al Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease. J Virol 2015; 89 (015) 7660-72.
• 57 Rodrigues CM, Sola S, Sharpe JC, Moura JJ, Steer CJ. Tauroursodeoxycholic acid prevents Bax-induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry 2003; 42 (010) 3070-80.
• 58 Rodrigues CM, Sola S, Silva R, Brites D. Bilirubin and amyloid-beta peptide induce cytochrome c release through mitochondrial membrane permeabilization. Mol Med 2000; 6 (011) 936-46.
• 59 Duan WM, Rodrigues CM, Zhao LR, Steer CJ, Low WC. Tauroursodeoxycholic acid improves the survival and function of nigral transplants in a rat model of Parkinson’s disease. Cell Transplant 2002; 11 (03) 195-205.
• 60 Elia AE, Lalli S, Monsurro MR, Sagnelli A, Taiello AC, Reggiori B. et al Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis. Eur J Neurol. 2016; 23 (01) 45-52.
• 61 Safety and Efficacy of TUDCA as add-on treatment in patients affected by ALS (TUDCA-ALS) 2019 [Available from: https://clinicaltrials.gov/ct2/show/record/NCT03800524.
• 62 Diaz-Amarilla P, Olivera-Bravo S, Trias E, Cragnolini A, Martinez-Palma L, Cassina P. et al Phenotypically aberrant astrocytes that promote motoneuron damage in a model of inherited amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2011; 108 (044) 18 126-31.
• 63 Trias E, Ibarburu S, Barreto-Nunez R, Babdor J, Maciel TT, Guillo M. et al Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis. J Neuroinflammation 2016; 13 (01) 177
• 64 Petrov D, Mansfield C, Moussy A, Hermine O. ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?. Front Aging Neurosci 2017; 9: 68
• 65 Filing of masitinib in the treatment of amyotrophic lateral sclerosis (ALS) to the European Medicines Agency (EMA) [press release] 2016
• 66 Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients 2019 [Available from: https://clinicaltrials.gov/ct2/show/record/NCT03127267.
• 67 Tonges L, Gunther R, Suhr M, Jansen J, Balck A, Saal KA. et al Rho kinase inhibition modulates microglia activation and improves survival in a model of amyotrophic lateral sclerosis. Glia 2014; 62 (02) 217-32.
• 68 Gunther R, Balck A, Koch JC, Nientiedt T, Sereda M, Bahr M. et al Rho Kinase Inhibition with Fasudil in the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis-Symptomatic Treatment Potential after Disease Onset. Front Pharmacol 2017; 8: 17
• 69 ROCK-ALS 2019 [Available from: rock-als.uni-goettingen.de
• 70 Inhibition of Rho Kinase (ROCK) With Fasudil as Disease-modifying Treatment for ALS (ROCK-ALS) 2019 [Available from: https://clinicaltrials.gov/ct2/show/record/NCT03792490.